Important progress has been made over the past decade or two in identifying molecular adaptations that occur in specific brain regions in response to chronic administration of drugs of abuse. It also has been possible, by use of genetic mutant mice and viral-mediated gene transfer, to directly implicate some of these molecular adaptations in specific behavioral features of addiction. There is a relative paucity of information, however, about the changes in synapses and neural circuits that occur as a consequence of these druginduced molecular changes. This information is critical for a thorough understanding of the neural mechanisms of addiction. Project 2 helps to fill this void by combining the molecular tools of mouse mutagenesis and viral gene transfer with state-of-the-art cellular electrophysiological recording techniques to examine changes in synaptic and membrane properties of NAc (nucleus accumbens) neurons elicited by known molecular adaptations in these neurons studied in the other Projects. We will focus on the cellular and synaptic effects of CREB and AFosB in NAc neurons. We have shown that CREB activation increases the intrinsic excitability of NAc neurons as well as their responses to glutamatergic stimulation, while inhibition of CREB activity exerts the opposite effects. The proposed studies will further characterize this regulation to better understand the underlying molecular mechanisms involved and to identify differences in CREB's effects in the two major subpopulations of NAc medium spiny neurons, those that predominantly express D^ dopamine receptors vs D2 dopamine receptors. Preliminary evidence suggests that AFosB exerts the opposite effect on NAc neurons, with prominent reductions in cell excitability seen. This is interesting in light of the opposite effects of AFosB vs CREB on gene expression in the NAc and on drug-regulated behaviors. We will now further explore the neurophysiological effects of AFosB, and its dominant negative antagonist AJunD, on NAc neurons, and study the underlying mechanisms, using newly developed tools in the Transgenic Core. This, too, will involve characterization of AFosB actions in DT vs D2 containing neurons. This Project thereby provides a crucial level of understanding for our PPG, by connecting molecular adaptations and complex behavior. Results from the proposed experiments will provide essential information about the cellular and synaptic changes that occur as a consequence of drug-induced changes in gene expression in NAc. This knowledge will in turn help us understand, at an increasingly sophisticated level, the neural mechanisms underlying the complex behavioral abnormalities that characterize drug abuse and addiction.